The Ca2+/Mn2+ ion-pump PMR1 links elevation of cytosolic Ca2+ levels to α-synuclein toxicity in Parkinson’s disease models
Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons, which arises from a yet elusive concurrence between genetic and environmental factors. The protein α -synuclein ( α Syn), the principle toxic effector in PD, has been shown to interfere with neuronal Ca 2...
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Published in | Cell death and differentiation Vol. 20; no. 3; pp. 465 - 477 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Nature Publishing Group
16.11.2012
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Subjects | |
Online Access | Get full text |
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Summary: | Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons, which arises from a yet elusive concurrence between genetic and environmental factors. The protein
α
-synuclein (
α
Syn), the principle toxic effector in PD, has been shown to interfere with neuronal Ca
2+
fluxes, arguing for an involvement of deregulated Ca
2+
homeostasis in this neuronal demise. Here, we identify the Golgi-resident Ca
2+
/Mn
2+
ATPase PMR1 (plasma membrane-related Ca
2+
-ATPase 1) as a phylogenetically conserved mediator of
α
Syn-driven changes in Ca
2+
homeostasis and cytotoxicity. Expression of
α
Syn in yeast resulted in elevated cytosolic Ca
2+
levels and increased cell death, both of which could be inhibited by deletion of PMR1. Accordingly, absence of PMR1 prevented
α
Syn-induced loss of dopaminergic neurons in nematodes and flies. In addition,
α
Syn failed to compromise locomotion and survival of flies when PMR1 was absent. In conclusion, the
α
Syn-driven rise of cytosolic Ca
2+
levels is pivotal for its cytotoxicity and requires PMR1. |
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Bibliography: | These authors contributed equally to this work. |
ISSN: | 1350-9047 1476-5403 |
DOI: | 10.1038/cdd.2012.142 |